L-Leucine

-1.52

log Kow = -1.52

-1.52

1.293 g/cu cm at 18 °C

White glistening hexagonal plates from aqueous alcohol

White crystals

21500

Leaflets from water. Sweet taste. Decomposes at 232 °C (also reported as 290 °C). Sublimes. pK1 = 2.36; pK2 = 9.60. Solubility in water (g/L): 7.97 (0 °C); 9.91 (25 °C); 14.06 (50 °C); 22.76 (75 °C); 42.06 (100 °C); in 90% alcohol: 1.3. Insoluble in ether. /Leucine DL-form/

Solubility in 99% alcohol: 0.72; in acetic acid: 10.9. Insoluble in ether.

Solubility in water (g/L): 22.7 (0 °C); 24.26 (25 °C); 28.87 (50 °C); 38.23 (75 °C); 56.38 (100 °C)

In water, 2.15X10+4 mg/L at 25 °C

21.5 mg/mL

Sublimes at 145-148 °C. Decomposes at 293-295 °C (rapid heating, sealed tube)

When heated to decomposition it emits toxic fumes of /nitric oxide/.

293

293 °C

268 - 288 °C

0.00000001 [mmHg]

Specific optical rotation: -10.8 at 25 °C/D (c = 2.2); +15.1 deg at 26 °C/D in 6N HCl (38 mols HCl per mol leucine); +7.6 deg at 20 °C/D in 3N NaOH (30 mols NaOH per mol leucine). Molecular rotation: +21.0 deg at /D (5NHCl); +29.5 deg /D (glacial acetic acid)

Dry Powder

White solid; [Merck Index] White powder; [Sigma-Aldrich MSDS]

Solid

Small white lustrous plates or crystalline powder; odourless

Positive

3.15

2.7

Agilent XCT

Electrospray ionization

formic acid (5.3nM)

2.38

9.61

2.35 (at 13 °C)

pKa = 2.35

This chemical does not meet GHS hazard criteria for 100% (208 of 208) of all reports.

Not Classified；Reported as not meeting GHS hazard criteria by 208 of 208 companies. For more detailed information, please visit ECHA C&L website.

Aggregated GHS information provided per 208 reports by companies from 2 notifications to the ECHA C&L Inventory.；Reported as not meeting GHS hazard criteria per 208 of 208 reports by companies.；There are 0 notifications provided by 0 of 208 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Chemical: L-Leucine

Regulation (EC) No 1831/2003 (amended)

L-Leucine is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of L-Leucine are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 07-04-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/11897

Leucine: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

L-Leucine: Does not have an individual approval but may be used under an appropriate group standard

IMAP assessments - L-Leucine: Environment tier I assessment；Evaluation - Chemicals that are unlikely to require further regulation to manage risks to human health

Teratogenicity and fetal loss observed in high dose animal studies; A more recent oral study of rats showed no adverse effects at 1,000 mg/kg during gestation; No human data available; [REPROTOX] Safe when used as a flavoring agent in food; [JECFA] May cause irritation; Shown to have tumor promoting activity for bladder carcinomas; [Sigma-Aldrich MSDS]

L-Leucine is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) any substance intended for use in or on food is of appropriate food grade and is prepared and handled as a food ingredient.

Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: leucine is included in weight control drug products.

Leucine used as a nutrient and/or dietary supplement in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice.

NAS, Food and Nutrition Board, Institute of Medicine; Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). National Academy Press, Washington, D.C. (2009).[Available from, as of March 10, 2010: http://www.nap.edu/catalog/10490.html]

Chemical: L-Leucine； Green circle - The chemical has been verified to be of low concern based on experimental and modeled data.

Not Classified

SRP: Criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

... High dietary levels of leucine suppressed the growth of rats fed a low protein diet, and the growth suppression could be prevented by supplementation with isoleucine and valine.

It has been well established that the branched chain amino acids (BCAA) compete with other large neutral amino acids (LNAA, particularly tryptophan and tyrosine) for membrane transport. Although the BCAA do not act as direct precursors for neurotransmitters, they can affect transport of certain LNAA across the blood-brain barrier, and thereby influence central nervous system concentrations of certain neurotransmitters.

Diets supplemented with glutamine, glutamine plus dihydroxyacetone, and glutamine plus dihydroxyacetone plus leucine were administered to male Sprague-Dawley rats for 1 wk. These are combinations that have been shown to stimulate hepatic glycogen synthesis in vitro. Food intake and body weight were monitored throughout the experiment. At the end of the feeding period, rats were fed a test meal and injected with 3H2O to measure in vivo rates of glycogen and lipid synthesis. Positional analysis of the 3H incorporated into glycogen was used to determine the proportion of glycogen synthesized via pyruvate. Final levels of plasma glucose and triacylglycerol and hepatic glycogen were also measured. Dietary glutamine increased hepatic glycogen synthesis. Addition of dihydroxyacetone, with or without additional leucine, caused an additional increase in hepatic glycogen synthesis and increased the proportion of glycogen synthesized via pyruvate. Lipogenesis was not altered in the liver or adipose tissue. None of the dietary treatments had any effect on food intake, but the diets that contained dihydroxyacetone decreased the rate of weight gain ...

Aging is characterized by a progressive loss of muscle mass that could be partly explained by a defect in the anabolic effect of food intake. ... This defect resulted from a decrease in the protein synthesis response to leucine in muscles from old rats. ... /This/ study assessed the effect of antioxidant supplementation on leucine-regulated protein metabolism in muscles from adult and old rats. Four groups of 8 and 20 mo old male /Wistar/ rats were supplemented or not for 7 wk with an antioxidant mixture containing rutin, vitamin E, vitamin A, zinc, and selenium. At the end of supplementation, muscle protein metabolism was examined in vitro using epitrochlearis muscles incubated with increasing leucine concentrations. In old rats, the ability of leucine to stimulate muscle protein synthesis was significantly decreased compared with adults. This defect was reversed when old rats were supplemented with antioxidants. It was not related to increased oxidative damage to 70-kDa ribosomal protein S6 kinase that is involved in amino acid signaling. These effects could be mediated through a reduction in the inflammatory state, which decreased with antioxidant supplementation ...

For more Interactions (Complete) data for L-Leucine (6 total), please visit the HSDB record page.

Safe in the present practices of use and concentration. Ingredient, concentration, and use information are available in documents discoverable at https://cir-reports.cir-safety.org

This group of essential amino acids are identified as the branched-chain amino acids, BCAAs. Because this arrangement of carbon atoms cannot be made by humans, these amino acids are an essential element in the diet. The catabolism of all three compounds initiates in muscle and yields NADH and FADH2 which can be utilized for ATP generation. The catabolism of all three of these amino acids uses the same enzymes in the first two steps. The first step in each case is a transamination using a single BCAA aminotransferase, with a-ketoglutarate as amine acceptor. As a result, three different a-keto acids are produced and are oxidized using a common branched-chain a-keto acid dehydrogenase, yielding the three different CoA derivatives. Subsequently the metabolic pathways diverge, producing many intermediates. The principal product from valine is propionylCoA, the glucogenic precursor of succinyl-CoA. Isoleucine catabolism terminates with production of acetylCoA and propionylCoA; thus isoleucine is both glucogenic and ketogenic. Leucine gives rise to acetylCoA and acetoacetylCoA, and is thus classified as strictly ketogenic. There are a number of genetic diseases associated with faulty catabolism of the BCAAs. The most common defect is in the branched-chain a-keto acid dehydrogenase. Since there is only one dehydrogenase enzyme for all three amino acids, all three a-keto acids accumulate and are excreted in the urine. The disease is known as Maple syrup urine disease because of the characteristic odor of the urine in afflicted individuals. Mental retardation in these cases is extensive. Unfortunately, since these are essential amino acids, they cannot be heavily restricted in the diet; ultimately, the life of afflicted individuals is short and development is abnormal The main neurological problems are due to poor formation of myelin in the CNS.

Plants with the highest amount of Leucine(1). [Table#7495]

Leucine is one of the nine indispensable amino acids that cannot be synthesized to meet body needs in animals and therefore must be provided in the diet(1).

L-Leucine is an essential branched-chain aliphatic amino acid found in many proteins. It is an isomer of leucine. It is important in hemoglobin synthesis and regulation of blood sugar and energy levels(1). /L-Leucine/

D-Leucine is an essential branched-chain amino acid important for hemoglobin formation(1). /D-Leucine/

/HUMAN EXPOSURE STUDIES/ ... Thirteen healthy subjects (6 men and 7 women) were studied on 4 different occasions. Subjects were admitted to the special diagnostic and treatment unit after a 12 hr fast. They received test meals at 8:00 am. On the first occasion, they received water only. Thereafter, they received 25 g glucose or 1 mmol/kg lean body mass leucine or 1 mmol/kg lean body mass leucine plus 25 g glucose in random order. Serum leucine, glucose, insulin, glucagon, and alpha-amino nitrogen concentrations were measured at various times during a 2.5 hr period after ingestion of the test meal. The amount of leucine provided was equivalent to that present in a high-protein meal, that is, that approximately present in a 350 g steak. After leucine ingestion, the leucine concentration increased 7-fold; and the alpha-amino nitrogen concentration increased by 16%. Ingested leucine did not affect the serum glucose concentration. When leucine was ingested with glucose, it reduced the 2.5 hr glucose area response by 50%. Leucine, when ingested alone, increased the serum insulin area response modestly. However, it increased the insulin area response to glucose by an additional 66%; that is, it almost doubled the response. Ingested leucine stimulated an increase in glucagon. Ingested glucose decreased it. When ingested together, the net effect was essentially no change in glucagon area. In summary, leucine at a dose equivalent to that present in a high-protein meal, had little effect on serum glucose or insulin concentrations but did increase the glucagon concentration. When leucine was ingested with glucose, it attenuated the serum glucose response and strongly stimulated additional insulin secretion. Leucine also attenuated the decrease in glucagon expected when glucose alone is ingested. The data suggest that a rise in glucose concentration is necessary for leucine to stimulate significant insulin secretion. This in turn reduces the glucose response to ingested glucose.

/OTHER TOXICITY INFORMATION/ There is no evidence that amino acids derived from usual or even high intakes of protein from foodstuffs present any risk.

/OTHER TOXICITY INFORMATION/ Dietary calcium modulation of adiposity is mediated, in part, by suppression of calcitriol, while the additional effect of dairy products is mediated by additional components; these include the high concentration of leucine, a key factor in the regulation of muscle protein turnover. We investigated the effect of leucine, calcitriol and calcium on energy metabolism in murine adipocytes and muscle cells and on energy partitioning between adipocytes and skeletal muscle. Leucine induced a marked increase in fatty acid oxidation in C2C12 muscle cells (p < 0.001) and decreased FAS expression by 66% (p < 0.001) in 3T3-L1 adipocytes. Calcitriol decreased muscle cell fatty acid oxidation by 37% (p < 0.001) and increased adipocyte FAS gene expression by threefold (p < 0.05); these effects were partially reversed by either leucine or calcium channel antagonism with nifedipine. Co-culture of muscle cells with adipocytes or incubation with 48 hr adipocyte conditioned medium decreased muscle fatty acid oxidation by 62% (p < 0.001), but treating adipocytes with leucine and/or nifedipine attenuated this effect. Leucine, nifedipine and calcitriol also modulated adiponectin production and thereby exerted additional indirect effects on fatty acid oxidation in C2C12 myotubes. Adiponectin increased IL-15 and IL-6 release by myotubes and partially reversed the inhibitory effects of calcitriol. Comparable effects of leucine, calcitriol and adiponectin were found in myotubes treated with conditioned medium derived from adipocytes or co-cultured with adipocytes. These data suggest that leucine and nifedipine promote energy partitioning from adipocytes to muscle cells, resulting in decreased energy storage in adipocytes and increasing fatty acid utilization in muscle.

/OTHER TOXICITY INFORMATION/ Studies both in vivo and in vitro have shown that leucine at a very high dose can stimulate muscle protein synthesis, an effect that is enhanced in vivo by insulin secreted in response to the leucine dose. High leucine can also inhibit protein degradation in skeletal muscle, as well as in liver. In contrast, at normal physiological levels, increasing leucine concentration by infusion stimulates muscle protein synthesis by enhancing its sensitivity to insulin. It is concluded that the role of leucine in vivo is to provide a signal that amino acids are available, which in combination with the signal of energy availability from insulin, stimulates muscle protein synthesis.

No indication of carcinogenicity to humans (not listed by IARC).

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Branched-chain amino acids (BCAA), Leu, and the signaling pathways they regulate have been reported to either improve or worsen adiposity and insulin sensitivity. Therefore, it is unclear whether dietary supplementation of Leu would be beneficial ... The effect of adding Leu (150 mmol/L; Expt. 1 and Expt. 2) or BCAA (109 mmol/L of each; Expt. 3) to the drinking water on diet-induced obesity (induced with a 60-kJ% fat diet) in singly housed C57BL6/J male mice for at least 14 wk. Liquid and solid food intakes were evaluated weekly along with body weight. During the last few weeks, several blood samples were taken at different times for plasma glucose, total cholesterol, or Leu measurements. Metabolic rate by indirect calorimetry, locomotor activity by light beam breaking, body composition by H1-NMR, and insulin tolerance were also determined. Compared with control, supplementation did not affect body weight, food intake, oxygen consumption, locomotor activity, body composition, insulin tolerance, or total cholesterol. In fed mice, this method of Leu supplementation only increased plasma Leu by 76% when the supplemented group was compared with control. On the other hand, after overnight food deprivation, the plasma Leu did not differ between these 2 groups, even though the mice in the supplemented group had continuous access to Leu-containing water during the solid food deprivation. Taken together, the results do not provide evidence that either Leu or BCAA supplementation of drinking water ameliorates diet-induced obesity in mice, although it may improve glycemia.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There is evidence that isoleucine acts as a promoter of urinary bladder carcinogenesis in rats. Thus, ... 6-week-old rats /were exposed/ to low doses of N-butyl-N (4-hydroxybutyl) nitrosamine (BHBN), a known initiator of cancer of the urinary bladder, and their diets /were supplemented/ with isoleucine or leucine. After 40 weeks, the incidence of papillomas was significantly elevated in rats receiving isoleucine plus BHBN over that observed in the group receiving BHBN alone.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a follow-up study of similar design, ... the experimental period /was extended/ to 60 weeks and included diets supplemented with 2 or 4% isoleucine or leucine. In this case, both dose levels of both amino acids significantly increased bladder carcinoma incidence over groups receiving BHBN alone or groups receiving amino acids alone (see Table). It thus appears that both leucine and isoleucine are potent promoters of bladder neoplasms in rats at dietary levels of 2% and above; a no-effect level was not identified in either of the above studies. There is no evidence that either amino acid is carcinogenic in the absence of an initiating agent. (a) = Dietary level refers to level of amino acid addition. N-butyl-N (4-hydroxybutyl) nitrosamine (BHNB) was administered at a dose below that known to induce bladder tumors. No papillomas or preneoplastic lesions were observed in the control groups or in the amino acid groups.；Table: Incidences of Bladder Carcinomas in Rats After 60 Weeks [Table#7494]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... Leucine is a teratogen when it is administered by intraperitoneal injection in pregnant female rats at doses as low as 15 mg/kg of body weight. The author suggested that the effects, which were multiple and serious, may have resulted from amino acid imbalances that adversely affected protein synthesis during embryonic development.

For more Non-Human Toxicity Excerpts (Complete) data for L-Leucine (13 total), please visit the HSDB record page.

Markedly elevated concentrations of branched chain amino acids (BCAA) and branched-chain alpha-keto acids are associated with maple-syrup urine disease; the latter is caused by an inborn error of metabolism in which branched-chain ketoacid dehydrogenase (BCKAD) is low or absent. BCAA imbalances appear not to cause these various diseases and physiological abnormalities, but rather result from them.

NIOSH (NOES Survey 1981-1983) has statistically estimated that 21,979 workers (16,153 of these were female) were potentially exposed to leucine in the US(1).

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

JECFA: ADI: Acceptable. No safety concern at current levels of intake when used as a flavoring agent.

LD50 Rat ip 5379 mg/kg

Chemical: L-Leucine

Regulation (EC) No 1831/2003 (amended)

L-Leucine is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of L-Leucine are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 07-04-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/11897

Leucine: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

L-Leucine: Does not have an individual approval but may be used under an appropriate group standard

L-Leucine is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) any substance intended for use in or on food is of appropriate food grade and is prepared and handled as a food ingredient.

Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: leucine is included in weight control drug products.

Leucine used as a nutrient and/or dietary supplement in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice.

Leucine is a branched-chain aliphatic amino acid that is an essential constituent of the diet.

Calculation of Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for Leucine for Children Ages 7 Months Through 18 Years [Table#7490]

Older views of the nutritional classification of amino acids categorized them into two groups: indispensable (essential) and dispensable (nonessential). The nine indispensable amino acids /(histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine)/ are those that have carbon skeletons that cannot be synthesized to meet body needs from simpler molecules in animals, and therefore must be provided in the diet. ...The definition of dispensable amino acids has become blurred as more information on the intermediary metabolism and nutritional characteristics of these compounds has accumulated. ... Dispensable amino acids /have been divided/ into two classes: truly dispensable and conditionally indispensable. Five amino acids /(alanine, aspartic acid, asparagine, glutamic acid, and serine)/ are termed dispensable as they can be synthesized in the body from either other amino acids or other complex nitrogenous metabolites. In addition, six other amino acids, including /(arginine, cysteine, glutamine, glycine, proline, and tyrosine)/, are conditionally indispensable as they are synthesized from other amino acids or their synthesis is limited under special pathophysiological conditions. This is even more of an issue in the neonate where it has been suggested that only alanine, aspartate, glutamate, serine, and probably asparagine are truly dietarily dispensable.

The term conditionally indispensable recognizes the fact that under most normal conditions the body can synthesize these amino acids to meet metabolic needs. However, there may be certain physiological circumstances: prematurity in the young infant where there is an inadequate rate at which cysteine can be produced from methionine; the newborn, where enzymes that are involved in quite complex synthetic pathways may be present in inadequate amounts as in the case of arginine, which results in a dietary requirement for this amino acid; or pathological states, such as severe catabolic stress in an adult, where the limited tissue capacity to produce glutamine to meet increased needs and to balance increased catabolic rates makes a dietary source of these amino acids required to achieve body nitrogen homeostasis. The cells of the small intestine become important sites of conditionally indispensable amino acid, synthesis, with some amino acids (e.g., glutamine and arginine) becoming nutritionally indispensable under circumstances of intestinal metabolic dysfunction. /Amino acids/

For more Bionecessity (Complete) data for L-Leucine (13 total), please visit the HSDB record page.

An essential amino acid. (Claim) Leucine helps with the regulation of blood-sugar levels, the growth and repair of muscle tissue (such as bones, skin and muscles), growth hormone production, wound healing as well as energy regulation. It can assist to prevent the breakdown of muscle proteins that sometimes occur after trauma or severe stress. It may also be beneficial for individuals with phenylketonuria - a condition in which the body cannot metabolize the amino acid phenylalanine

This group of essential amino acids are identified as the branched-chain amino acids, BCAAs. Because this arrangement of carbon atoms cannot be made by humans, these amino acids are an essential element in the diet. The catabolism of all three compounds initiates in muscle and yields NADH and FADH2 which can be utilized for ATP generation. The catabolism of all three of these amino acids uses the same enzymes in the first two steps. The first step in each case is a transamination using a single BCAA aminotransferase, with a-ketoglutarate as amine acceptor. As a result, three different a-keto acids are produced and are oxidized using a common branched-chain a-keto acid dehydrogenase, yielding the three different CoA derivatives. Subsequently the metabolic pathways diverge, producing many intermediates. The principal product from valine is propionylCoA, the glucogenic precursor of succinyl-CoA. Isoleucine catabolism terminates with production of acetylCoA and propionylCoA; thus isoleucine is both glucogenic and ketogenic. Leucine gives rise to acetylCoA and acetoacetylCoA, and is thus classified as strictly ketogenic. There are a number of genetic diseases associated with faulty catabolism of the BCAAs. The most common defect is in the branched-chain a-keto acid dehydrogenase. Since there is only one dehydrogenase enzyme for all three amino acids, all three a-keto acids accumulate and are excreted in the urine. The disease is known as Maple syrup urine disease because of the characteristic odor of the urine in afflicted individuals. Mental retardation in these cases is extensive. Unfortunately, since these are essential amino acids, they cannot be heavily restricted in the diet; ultimately, the life of afflicted individuals is short and development is abnormal The main neurological problems are due to poor formation of myelin in the CNS.

The mechanism of intracellular protein degradation, by which protein is hydrolyzed to free amino acids, is more complex and is not as well characterized at the mechanistic level as that of synthesis. A wide variety of different enzymes that are capable of splitting peptide bonds are present in cells. However, the bulk of cellular proteolysis seems to be shared between two multienzyme systems: the lysosomal and proteasomal systems. The lysosome is a membrane-enclosed vesicle inside the cell that contains a variety of proteolytic enzymes and operates mostly at acid pH. Volumes of the cytoplasm are engulfed (autophagy) and are then subjected to the action of the protease enzymes at high concentration. This system is thought to be relatively unselective in most cases, although it can also degrade specific intracellular proteins. The system is highly regulated by hormones such as insulin and glucocorticoids, and by amino acids. The second system is the ATP-dependent ubiquitin-proteasome system, which is present in the cytoplasm. The first step is to join molecules of ubiquitin, a basic 76-amino acid peptide, to lysine residues in the target protein. Several enzymes are involved in this process, which selectively targets proteins for degradation by a second component, the proteasome.

Dietary leucine transported into the brain parenchyma serves several functions. Most prominent is the role of leucine as a metabolic precursor of fuel molecules, alpha-ketoisocaproate and ketone bodies. As alternatives to glucose, these compounds are forwarded by the producing astrocytes to the adjacent neural cells. Leucine furthermore participates in the maintenance of the nitrogen balance in the glutamate/glutamine cycle pertinent to the neurotransmitter glutamate. Leucine also serves as a regulator of the activity of some enzymes important for brain energy metabolism. Another role of leucine as an informational molecule is in mTOR signaling that participates in the regulation of food ingestion. The importance of leucine for brain function is stressed by the fact that inborn errors in its metabolism cause metabolic diseases often associated with neuropathological symptoms. In this overview, the current knowledge on the metabolic and regulatory roles of this essential amino acid in neural cells are briefly summarized.

Ingestion of a leucine-enriched essential amino acid nutrient solution rapidly and potently activates the mammalian target of rapamycin signalling pathway and protein synthesis in human skeletal muscle. Further, mTOR signalling and muscle protein synthesis are enhanced when leucine-enriched nutrients are ingested following resistance exercise. The addition of leucine to regular meals may improve the ability of feeding to stimulate protein synthesis in old human muscle. ... Leucine and essential amino acids appear to stimulate human muscle protein synthesis primarily by activating the mammalian target of rapamycin signalling pathway. How human muscle cells sense an increase in leucine and/or essential amino acids to activate mammalian target of rapamycin signalling is currently unknown. Recent work, however, suggests that the kinases hVps34 and MAP43K may be involved. Leucine-enriched essential amino acid ingestion, in combination with resistance exercise in some cases, may be a useful intervention to promote mTOR signalling and protein synthesis in an effort to counteract a variety of muscle wasting conditions (e.g. sarcopenia, cachexia, AIDS, inactivity/bed rest, sepsis, kidney failure, and trauma).

One of the amino acids most affected by exercise is the branched-chain amino acid leucine. ... Leucine appears to exert a synergistic role with insulin as a regulatory factor in the insulin/ phosphatidylinositol-3 kinase (PI3-K) signal cascade. Insulin serves to activate the signal pathway, while leucine is essential to enhance or amplify the signal for protein synthesis at the level of peptide initiation. Studies feeding amino acids or leucine soon after exercise suggest that post-exercise consumption of amino acids stimulates recovery of muscle protein synthesis via translation regulations ...

For more Mechanism of Action (Complete) data for L-Leucine (12 total), please visit the HSDB record page.

The branched-chain amino acids (BCAA) -- leucine, isoleucine, and valine -- differ from most other indispensable amino acids in that the enzymes initially responsible for their catabolism are found primarily in extrahepatic tissues. Each undergoes reversible transamination, catalyzed by a branched-chain aminotransferase (BCAT), and yields alpha-ketoisocaproate (KIC, from leucine), alpha-keto-beta-methylvalerate (KMV, from isoleucine), and alpha-ketoisovalerate (KIV, from valine). Each of these ketoacids then undergoes an irreversible, oxidative decarboxylation, catalyzed by a branchedchain ketoacid dehydrogenase (BCKAD). The latter is a multienzyme system located in mitochondrial membranes. The products of these oxidation reactions undergo further transformations to yield acetyl CoA, propionyl CoA, acetoacetate, and succinyl CoA; the BCAA are thus keto- and glucogenic.

Once the amino acid deamination products enter the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle or Krebs cycle) or the glycolytic pathway, their carbon skeletons are also available for use in biosynthetic pathways, particularly for glucose and fat. Whether glucose or fat is formed from the carbon skeleton of an amino acid depends on its point of entry into these two pathways. If they enter as acetyl-CoA, then only fat or ketone bodies can be formed. The carbon skeletons of other amino acids can, however, enter the pathways in such a way that their carbons can be used for gluconeogenesis. This is the basis for the classical nutritional description of amino acids as either ketogenic or glucogenic (ie, able to give rise to either ketones [or fat] or glucose). Some amino acids produce both products upon degradation and so are considered both ketogenic and glucogenic. /Amino acids/

Kinetics of leucine and its oxidation were determined in human pregnancy and in the newborn infant, using stable isotopic tracers, to quantify the dynamic aspects of protein metabolism. These data show that in human pregnancy there is a decrease in whole-body rate of leucine turnover compared with nonpregnant women. In addition, data in newborn infants show that leucine turnover expressed as per kg body weight is higher compared with adults. The administering of nutrients resulted in a suppression of the whole-body rate of proteolysis ... The relations among the transamination of leucine, leucine N kinetics, and urea synthesis and glutamine kinetics in human pregnancy and newborn infants /were also examined/. In human pregnancy, early in gestation, there is a significant decrease in urea synthesis in association with a decrease in the rate of transamination of leucine. A linear correlation was evident between the rate of leucine reamination and urea synthesis during fasting in pregnant and nonpregnant women. In healthy-term newborn and growing infants, although the reamination of leucine was positively related to glutamine flux, leucine reamination was negatively related to urea synthesis, suggesting a redirection of amino N toward protein accretion ...

The metabolic disease 3-methylglutaconic aciduria type I (MGA1) is characterized by an abnormal organic acid profile in which there is excessive urinary excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid. Affected individuals display variable clinical manifestations ranging from mildly delayed speech development to severe psychomotor retardation with neurological handicap. MGA1 is caused by reduced or absent 3-methylglutaconyl-coenzyme A (3-MG-CoA) hydratase activity within the leucine degradation pathway. The human AUH gene has been reported to encode for a bifunctional enzyme with both RNA-binding and enoyl-CoA-hydratase activity. In addition, it was shown that mutations in the AUH gene are linked to MGA1 ...

For more Metabolism/Metabolites (Complete) data for L-Leucine (8 total), please visit the HSDB record page.

Although the free amino acids dissolved in the body fluids are only a very small proportion of the body's total mass of amino acids, they are very important for the nutritional and metabolic control of the body's proteins. ... Although the plasma compartment is most easily sampled, the concentration of most amino acids is higher in tissue intracellular pools. Typically, large neutral amino acids, such as leucine and phenylalanine, are essentially in equilibrium with the plasma. Others, notably glutamine, glutamic acid, and glycine, are 10- to 50-fold more concentrated in the intracellular pool. Dietary variations or pathological conditions can result in substantial changes in the concentrations of the individual free amino acids in both the plasma and tissue pools.

Table: Comparison of the Pool Sizes of Free and Protein-Bound Amino Acids in Rat Muscle [Table#7489]

A kinetic modeling of leucine plasma concentration changes is proposed to describe the plasma leucine reduction rate during continuous extracorporeal removal therapy (CECRT) in neonates with maple syrup urine disease. Data were obtained from seven neonates using a bicompartmental model for the best fitted curve of plasma leucine decrease during CECRT. During the first 3 hr, leucine plasma levels decreased according to an exponential curve: [Leu](t) = [Leu](i) x 0.95 x 10(-0.09t) where [Leu](t) is the leucine plasma level (umol/L) at time t (hr) during CECRT and [Leu](I) is the initial plasma level. From hr 4 to the end of CECRT, a second exponential curve was observed: [Leu](t) = [Leu](i) x 0.74 x 10(-0.05t). Plasma leucine levels obtained from three other neonates were similar to those predicted by the model. The apparent distribution volumes for leucine that correspond to the two exponential equations obtained were calculated from the leucine mass removal collected in the spent dialysate and ultrafiltrate. The distribution volume was 34 +/- 3% of body weight during the first 3 h of CECRT and 72 +/- 7% from hr 4 to the end of CECRT. These figures are similar to known values for the extracellular water compartment and for total body water in the newborn. The findings suggest that leucine handling during CECRT is similar to that of nonprotein-bound small-molecular-weight solutes such as urea.

The transport of L-leucine by two human breast cancer cell lines has been examined. L-leucine uptake by MDA-MB-231 and MCF-7 cells was via a BCH-sensitive, Na+ -independent pathway. L-leucine uptake by both cell lines was inhibited by L-alanine, D-leucine and to a lesser extent by L-lysine but not by L-proline. Estrogen (17beta-estradiol) stimulated L-leucine uptake by MCF-7 but not by MDA-MB-231 cells. L-leucine efflux from MDA-MB-231 and MCF-7 cells was trans-stimulated by BCH in a dose-dependent fashion. The effect of external BCH on L-leucine efflux from both cell types was almost abolished by reducing the temperature from 37 to 4 degrees C. There was, however, a significant efflux of L-leucine under zero-trans conditions which was also temperature-sensitive. L-glutamine, L-leucine, D-leucine, L-alanine, AIB and L-lysine all trans-stimulated L-leucine release from MDA-MB-231 and MCF-7 cells. In contrast, D-alanine and L-proline had little or no effect. The anti-cancer agent melphalan inhibited L-leucine uptake by MDA-MB-231 cells but had no effect on L-leucine efflux. Quantitative real-time PCR revealed that LAT1 mRNA was approximately 200 times more abundant than LAT2 mRNA in MCF-7 cells and confirmed that MDA-MB-231 cells express LAT1 but not LAT2 mRNA. LAT1 mRNA levels were higher in MCF-7 cells than in MDA-MB-231 cells. Furthermore, LAT1 mRNA was more abundant than CD98hc mRNA in both MDA-MB-231 and MCF-7 cells. The results suggest that system L is the major transporter for L-leucine in both MDA-MB-231 and MCF-7 cells. It is possible that LAT1 may be the major molecular correlate of system L in both cell types. However, not all of the properties of system L reflected those of LAT1/LAT2/CD98hc.

For more Absorption, Distribution and Excretion (Complete) data for L-Leucine (7 total), please visit the HSDB record page.

Adipose Tissue；Adrenal Medulla；Bladder；Epidermis；Fibroblasts；Intestine；Kidney；Neuron；Placenta；Platelet；Prostate；Skeletal Muscle；Testis

Extracellular；Mitochondria

2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency；3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency；3-hydroxyisobutyric acid dehydrogenase deficiency；3-hydroxyisobutyric aciduria；3-Methylcrotonyl Coa Carboxylase Deficiency Type I；3-Methylglutaconic Aciduria Type I；3-Methylglutaconic Aciduria Type III；3-Methylglutaconic Aciduria Type IV；Amikacin Action Pathway；Arbekacin Action Pathway；Total 50 pathways, visit the HMDB page for details

CIR ingredient: Leucine

An essential amino acid; [Merck Index] Used as a flavoring agent and nutritional supplement for foods; [FDA] Used in biochemical research; [HSDB]

Nutrient and dietary supplement, biochemical research

Nutrient

BIOLOGICAL ACTIVITY: Antiencephalopathic

Reported uses；Table: Reported uses (ppm): (Flavor and Extract Manufacturers' Association) [Table#7497]

Heavy metals (as Pb): not more than 0.002%; Lead: not more than 10 mg/kg; Ash: not more than 0.1%

2023: 41,827 lb；2022: 53,668 lb；2021: 74,021 lb；2020: 58,051 lb

Production volumes for non-confidential chemicals reported under the Inventory Update Rule. [Table#7496]

Catalyst

Catalyst

Hydrolysis of protein (edestin, hemoglobin, zein), organic synthesis from the alpah-bromo acid.

By bromination followed by amination of isocaproic acid; via the acetamidomalonic ester; by isolation from gluten, casein, keratin; from hydantoin.

EPA Safer Chemical Functional Use Classes -> Processing Aids and Additives

Safer Chemical Classes -> Green circle - The chemical has been verified to be of low concern

Flavouring Agent -> FLAVOURING_AGENT -> JECFA Functional Classes

Flavoring Agents -> JECFA Flavorings Index

Cosmetics -> Antistatic; Skin conditioning; Hair conditioning

Pharmaceutical and Medicine Manufacturing

L-Leucine: ACTIVE

Leucine: ACTIVE

The amino acids that are incorporated into mammalian protein are alpha-amino acids, with the exception of proline, which is an alpha-imino acid. This means that they have a carboxyl group, an amino nitrogen group, and a side chain attached to a central alpha-carbon. Functional differences among the amino acids lie in the structure of their side chains. In addition to differences in size, these side groups carry different charges at physiological pH (e.g., nonpolar, uncharged but polar, negatively charged, positively charged); some groups are hydrophobic (e.g., branched chain and aromatic amino acids) and some hydrophilic (most others). These side chains have an important bearing on the ways in which the higher orders of protein structure are stabilized and are intimate parts of many other aspects of protein function.